It is the broad, long-term goal of this program to build on and extend current knowledge in the field of stem cell transplantation with a focus on hemato-lymphoid diseases. While the use of high dose therapy with hematopoietic support has resulted in improved outcome in selected patients, the relapse rate in those treated late in the course of their disease remains high. To this end, the investigators of this renewal application will utilize the approach of translational research, bridging novel experimental concepts and observations made at the laboratory bench to clinical application at the patient's bedside. This program project will focus on the use and understanding of stem cell transplantation in an attempt to achieve a complete or near complete remission followed by novel manipulations to maintain the remission, thus improving the clinical outcome for our patients. The major hypothesis to be tested is whether a step wise process in engineering a haploidentical graft will ensure donor engraftment without graft-versus-host disease (GVHD) but at the same time, enhancing immune recovery and anti tumor effects of the allogeneic transplant. Project I will focus on the clinical projects to improve the outcomes of haploidentical transplantation and post transplant cellular strategies. Project II will continue to develop the use of naive T cell depletion to decrease GVHD and ascertain if memory T cells can enhance immune recovery. Project will determine the utility of toll like receptors (TLRs) in enhancing vaccine strategies. The interplay of innate and the adaptive immune system with the process of graft engineering and adoptive cellular therapy is a major strength of the scientists in this application. The extensive on going discussions and the strong interactions among the projects and cores create an exciting synergy that will lead to important results. Our commitment to patients'welfare and improved outcomes continues to drive our efforts. The lessons learned from these studies will also be applicable to other forms of allogeneic hematopoietic cell transplantation.